Biology subjects

Subramanian, S.

Publications and source records attributed to Subramanian, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma

The sub-ventricular zone (SVZ) is the most well-characterized neurogenic area in the mammalian brain. We previously showed that in 65% of patients with glioblastoma (GBM), the SVZ is a reservoir of cancer stem-like cells that contribute to treatment resistance and emergence of recurrence. Here, we built a single-nucleus RNA-sequencing-based microenvironment landscape of the tumor mass (T_Mass) and the SVZ (T_SVZ) of 15 GBM patients and 2 histologically normal SVZ (N_SVZ) samples as controls. We identified a mesenchymal signature in the T_SVZ of GBM patients: tumor cells from the T_SVZ relied on the ZEB1 regulatory network, whereas tumor cells in the T_Mass relied on the TEAD1 regulatory network. Moreover, the T_SVZ microenvironment was predominantly characterized by tumor-supportive microglia, which spatially co-exist and establish heterotypic interactions with tumor cells. Lastly, differential gene expression analyses, predictions of ligand-receptor and incoming/outgoing interactions, and functional assays revealed that the IL-1{beta}/IL-1RAcP and Wnt-5a/Frizzled-3 pathways are therapeutic targets in the T_SVZ microenvironment. Our data provide insights into the biology of the SVZ in GBM patients and identify specific targets of this microenvironment.

cancer biology↗

bioRxiv2024

Sex-specific sub-lethal effects of low virulence entomopathogenic fungi may boost the Sterile Insect Technique

BACKGROUNDThe Sterile Insect Technique (SIT) is a species-specific method for controlling insect pests. Recent studies have explored the combination of SIT with entomopathogenic microorganisms, known as boosted-SIT, to enhance its effectiveness. This study aimed to evaluate the potential of the entomopathogenic fungi, Metarhizium anisopliae, in boosting the SIT for managing the oriental fruit fly, Bactrocera dorsalis. METHODSAdult flies from a laboratory population of B. dorsalis were inoculated with one of eight strains of M. anisopliae to assess fungus virulence in each sex. Ideally, boosted-SIT should minimally impact sterile males and reduce female fecundity maximally. A brief exposure to fungal spores was efficient to infect males, and for them to transmit the fungus to females when hosted together for 24 hours. RESULTSOur results showed significant variations in the mortality induced by the strains in males, but not in females that exhibited low mortality. Strains varied in their sub-lethal effects on female fecundity, with almost a two-fold variation among strains. Furthermore, strains that had the lowest virulence on males tended to reduce female fecundity the most. CONCLUSIONOur study brings a proof of concept that it is possible to leverage boosted- SIT using carefully selected pathogen strains and their sub-lethal effects on both the male and female fruit fly.

ecology↗

bioRxiv2024

Antibody-drug conjugates targeting EGFR ligand Epiregulin inhibit colorectal tumor growth irrespective of RAS mutational status

As colorectal cancer (CRC) remains a leading cause of cancer-related death, identifying therapeutic targets and approaches is essential to improve patient outcomes. The EGFR ligand epiregulin (EREG) is highly expressed in RAS wildtype and mutant CRC with minimal expression in normal tissues, making it an attractive target for antibody-drug conjugate (ADC) development. In this study, we produced and purified an EREG monoclonal antibody (mAb), H231, that had high specificity and affinity for human and mouse EREG. H231 also internalized to lysosomes, which is important for ADC payload release. ImmunoPET and ex vivo biodistribution studies showed significant tumor uptake of 89Zr-labeled H231 with minimal uptake in normal tissues. H231 was conjugated to either cleavable dipeptide or tripeptide chemical linkers attached to the DNA-alkylating payload duocarmycin DM, and cytotoxicity of EREG ADCs was assessed in a panel of CRC cell lines. EREG ADCs incorporating tripeptide linkers demonstrated the highest potency in EREG-expressing CRC cells irrespective of RAS mutations. Preclinical safety and efficacy studies showed EREG ADCs were well-tolerated, neutralized EGFR pathway activity, caused significant tumor growth inhibition or regression, and increased survival in CRC cell line and patient-derived xenograft models. These data suggest EREG is a promising target for the development of ADCs for treating CRC and other cancer types that express high levels of EREG. While the efficacy of clinically approved anti-EGFR mAbs are largely limited by RAS mutational status, EREG ADCs may show promise for both RAS mutant and wildtype patients, thus improving existing treatment options. Significance: EREG-targeting antibody-drug conjugates demonstrate acceptable safety and robust therapeutic efficacy in RAS mutant and wildtype colorectal cancer, suggesting their potential as an alternative to EGFR-targeted therapy to benefit a broader patient population.

cancer biology↗

bioRxiv2023

Oligodendrocytes and neurons contribute to amyloid-β deposition in Alzheimer's disease

In Alzheimers disease (AD), amyloid-{beta} (A{beta}) is thought to be of neuronal origin. However, in single-cell RNAseq datasets from mouse and human, we found transcripts of amyloid precursor protein (APP) and the amyloidogenic-processing machinery equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that almost a third of cortical A{beta} deposited in plaques is derived from OLs. However, excitatory projection neurons must provide a threshold level of A{beta} production for plaque deposition to occur and for oligodendroglial A{beta} to co-aggregate. Indeed, very few plaques are deposited in the absence of neuronally-derived A{beta}, although soluble A{beta} species are readily detected, especially in subcortical white matter. Our data identify OLs as a source of A{beta} in vivo and further underscore a non-linear relationship between cellular A{beta} production and resulting plaque formation. Ultimately, our observations are relevant for therapeutic strategies aimed at disease prevention in AD.

neuroscience↗

bioRxiv2023

Effects of Firefighter Helmets on Cervical Intervertebral Kinematics: An OpenSim-Based Biomechanical Study

The assessment of cervical intervertebral kinematics can serve as the basis for understanding any degenerative changes in the cervical spine due to the prolonged wear of a heavyweight, imbalanced firefighting helmet. Therefore, this study aimed to analyze cervical intervertebral kinematics using OpenSim musculoskeletal modeling platform in order to provide much-needed insights of how the inertial properties of firefighter helmet affect cervical spinal mobility. A total of 36 firefighters (18 males and 18 females) were recruited to perform static and dynamic neck flexion, extension, and left and right lateral bending tasks for three conditions: 1) no-helmet, 2) US-style helmet with a comparatively superior center of mass (COM), and 3) European-style helmet with relatively higher mass but an inferior COM. Three custom-made OpenSim head-neck models were created to calculate cervical intervertebral kinematics for each helmet condition. Results showed that the helmet use significantly (p<0.001) affects neck and cervical spinal kinematics. Especially, the superior COM placement in the US-style helmet, despite its lighter weight, caused more pronounced kinematic changes and quicker attainment of peak flexion and extension angles compared to the European-style helmet across all cervical joints. Moreover, results also revealed discrepancies between OpenSim-derived neck and cervical range-of-motion and those reported in previous in-vivo studies. In conclusion, the present study underscores the importance of designing firefighter helmets with a lower profile (less superior COM) to enhance neck range of motion and minimize potential neck injuries.

bioengineering↗

bioRxiv2023

Adaptive capacity of a DNA polymerase clamp-loader ATPase complex

The ability of mutations to facilitate adaptation is central to evolution. To understand how mutations can lead to functional adaptation in a complex molecular machine, we created a defective version of the T4 clamp-loader complex, which is essential for DNA replication. This variant, which is [~]5000-fold less active than the wildtype, was made by replacing the catalytic domains with those from another phage. A directed-evolution experiment revealed that multiple substitutions to a single negatively-charged residue in the chimeric clamp loader - Asp 86 - restore fitness to within [~]20-fold of wildtype. These mutations remove an adventitious electrostatic repulsive interaction between Asp 86 and the sliding clamp. Deep mutagenesis shows that the reduced fitness of the chimeric clamp loader is compensated for by lysine and arginine substitutions of several DNA-proximal residues in the clamp loader or the sliding clamp. Thus, the fitness decrease of the chimeric clamp loader is caused by a reduction in affinity between the clamp loader and the clamp. Our results demonstrate that there is a latent capacity for increasing affinity of the clamp loader for DNA and the sliding clamp, such that even single point mutations can readily compensate for the loss of function due to suboptimal interactions elsewhere.

biochemistry↗

bioRxiv2023

Genomic consequences of isolation and inbreeding in an island dingo population

Dingoes come from an ancient canid lineage that originated in East Asia around 8000-11,000 years BP. As Australias largest terrestrial predator, dingoes play an important ecological role. A small, protected population exists on a world heritage listed offshore island, Kgari (formerly Fraser Island). Concern regarding the persistence of dingoes on Kgari has risen due to their low genetic diversity and elevated inbreeding levels. However, whole-genome sequencing data is lacking from this population. Here, we include five new whole-genome sequences of Kgari dingoes. We analyze a total of 18 whole genome sequences of dingoes sampled from mainland Australia and Kgari to assess the genomic consequences of their demographic histories. Long (>1 Mb) runs of homozygosity (ROH) -- indicators of inbreeding -- are elevated in all sampled dingoes. However, Kgari dingoes showed significantly higher levels of very long ROH (>5 Mb), providing genomic evidence for small population size, isolation, inbreeding, and a strong founder effect. Our results suggest that, despite current levels of inbreeding, the Kgari population is purging strongly deleterious mutations, which, in the absence of further reductions in population size, may facilitate the persistence of small populations despite low genetic diversity and isolation. However, there may be little to no purging of mildly deleterious alleles, which may have important long-term consequences, and should be considered by conservation and management programs. SIGNIFICANCEA long-standing question in conservation genetics is whether long-term isolation and elevated levels of inbreeding always leads to inevitable population extinction. Here we conduct the first-ever whole-genome analysis of a population of dingoes living in long-term isolation on an island off the coast of Australia (Kgari). We show that these animals are beset by very low genetic diversity, likely the result of extensive inbreeding, and an elevated number of deleterious homozygotes. However, our results suggest that these dingoes are likely purging highly deleterious alleles, which may have allowed them to persist long term despite their extremely small population (<200 individuals).

evolutionary biology↗

bioRxiv2023

IMPROVING ANTIBODY AFFINITY USING LABORATORYDATA WITH LANGUAGE MODEL GUIDED DESIGN

AO_SCPLOWBSTRACTC_SCPLOWProtein design involves navigating vast sequence spaces to discover sequences with desired traits. Language models (LMs) pretrained on universal protein datasets have shown potential to make this search space tractable. However, LMs trained solely on natural sequences have limitations in creating proteins with novel functions. In this work, we used a combination of methods to finetune pretrained LMs on laboratory data collected in an anti-CD40L single domain antibody library campaign to develop an ensemble scoring function to model the fitness landscape and guide the design of new antibodies. Laboratory experiments confirmed improved CD40L affinity in the designed antibodies. Notably, the designs improved the affinities of four antibodies, originally ranging from 1 nanomolar to 100 picomolar, all to below 25 picomolar, approaching the limit of detection. This work is a promising step towards realizing the potential of LMs to leverage laboratory data to develop improved treatments for diseases.

synthetic biology↗

bioRxiv2023

Allogeneic Tumor Cell-Derived Extracellular Vesicles Stimulate CD8 T Cell Response in Colorectal Cancer

Colorectal Cancer (CRC) is the second leading cause of cancer-related death in the United States. Most CRC patients present with a microsatellite stable (MSS) phenotype and are highly resistant to immunotherapies. Tumor extracellular vesicles (TEVs), secreted by tumor cells, can contribute to intrinsic resistance to immunotherapy in CRC. We previously showed that autologous TEVs without functional miR-424 induce anti-tumor immune responses. We hypothesized that allogeneic modified CRC-TEVs without miR-424 (mouse homolog miR-322) derived from an MC38 background would effectively stimulate CD8+ T cell response and limit CT26 tumor growth. Here we show that prophylactic administration of MC38 TEVs without functional miR-424 significantly increased CD8+ T cells in CT26 CRC tumors and limited tumor growth, not B16-F10 melanoma tumors. We further show that the depletion of CD4+ and CD8+ T cells abolished the protective effects of MC38 TEVs without functional miR-424. We further show that TEVs can be taken up by DCs in vitro, and subsequent prophylactic administration of autologous DCs exposed to MC38 TEVs without functional miR-424 suppressed tumor growth and increased CD8+ T cells compared to MC38 wild-type TEVs exposed to DCs, in Balb/c mice bearing CT26 tumors. Notably, the modified EVs were well tolerated and did not increase cytokine expression in peripheral blood. These findings suggest that allogeneic-modified CRC-EVs without immune suppressive miR-424 can induce antitumor CD8+ T cell responses and limit tumor growth in vivo.

cancer biology↗

bioRxiv2023

Cell Type-Specific Regulation by a Heptad of Transcription Factors in Human Hematopoietic Stem and Progenitor Cells

Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay of transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs - FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2 - bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remained unknown. We mapped genome-wide chromatin contacts and TF binding profiles in HSPC subsets (HSC, CMP, GMP, MEP) and found that heptad occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. These findings suggest that specific heptad-TF combinations play critical roles in regulating hematopoietic differentiation and provide a valuable resource for development of targeted therapies to manipulate specific HSPC subsets.

developmental biology↗

bioRxiv2023

A Vibrio cholerae viral satellite maximizes its spread and inhibits phage by remodeling hijacked phage coat proteins into small capsids

Phage satellites commonly remodel capsids they hijack from the phages they parasitize, but only a few mechanisms regulating the change in capsid size have been reported. Here, we investigated how a satellite from Vibrio cholerae, PLE, remodels the capsid it has been predicted to steal from the phage ICP1 (1). We identified that a PLE-encoded protein, TcaP, is both necessary and sufficient to form small capsids during ICP1 infection. Interestingly, we found that PLE is dependent on small capsids for efficient transduction of its genome, making it the first satellite to have this requirement. ICP1 isolates that escaped TcaP-mediated remodeling acquired substitutions in the coat protein, suggesting an interaction between these two proteins. With a procapsid-like-particle (PLP) assembly platform in Escherichia coli, we demonstrated that TcaP is a bona fide scaffold that regulates the assembly of small capsids. Further, we studied the structure of PLE PLPs using cryogenic electron microscopy and found that TcaP is an external scaffold, that is functionally and somewhat structurally similar to the external scaffold, Sid, encoded by the unrelated satellite P4 (2). Finally, we showed that TcaP is largely conserved across PLEs. Together, these data support a model in which TcaP directs the assembly of small capsids comprised of ICP1 coat proteins, which inhibits the complete packaging of the ICP1 genome and permits more efficient packaging of replicated PLE genomes.

microbiology↗

bioRxiv2023

Genomic signatures of bottleneck and founder effects in dingoes

Dingoes arrived in Australia during the mid-Holocene and are the native top-order terrestrial predator on the mainland and some offshore islands. Although dingoes subsequently spread across the continent, the initial founding population(s) could have been small. To investigate this hypothesis, we examined the potential signatures of bottlenecks and founder effects in dingoes by sequencing the whole genomes of three dingoes and also obtaining the genome data from nine additional dingoes and 56 canines, including wolves, village dogs and breed dogs, and examined the signatures of bottlenecks and founder effects. We found that the nucleotide diversity of dingoes was low, and 36% less than highly inbred breed dogs and 3.3 times lower than wolves. The number of runs of homozygosity (RoH) segments in dingoes was 1.6 to 4.7 times higher than in other canines. Whilst examining deleterious mutational load, we observed that dingoes carried elevated ratios of nonsynonymous-to-synonymous diversities, significantly higher numbers of homozygous deleterious Single Nucleotide Variants (SNVs), and increased numbers of loss of function SNVs, compared to breed dogs, village dogs, and wolves. These results suggest dingoes experienced a severe bottleneck, potentially caused by the limited number of founding individuals. While many studies observe less diversity and a higher number of deleterious mutations in domesticated populations compared to their wild relatives, we observed the opposite - .i.e. wild dingoes have lower diversity and a greater number of harmful mutations than domesticated dogs. Our findings can be explained by bottlenecks and founder effects during the establishment of dingoes on mainland Australia. These findings highlight the need for conservation-based management of dingoes and need for wildlife managers to be cognisant of these findings when considering the use of lethal control measures across the landscape.

evolutionary biology↗

bioRxiv2023

Therapeutic and vaccine-induced cross-reactive antibodies with effector function against emerging Omicron variants

Currently circulating SARS-CoV-2 variants acquired convergent mutations at receptor-binding domain (RBD) hot spots1. Their impact on viral infection, transmission, and efficacy of vaccines and therapeutics remains poorly understood. Here, we demonstrate that recently emerged BQ.1.1. and XBB.1 variants bind ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1 and XBB.1 RBDs bound to human ACE2 and S309 Fab (sotrovimab parent) explain the altered ACE2 recognition and preserved antibody binding through conformational selection. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1, the variant displaying the greatest loss of neutralization. Moreover, in several donors vaccine-elicited plasma antibodies cross-react with and trigger effector functions against Omicron variants despite reduced neutralizing activity. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring persistent immune imprinting. Our findings suggest that this previously overlooked class of cross-reactive antibodies, exemplified by S309, may contribute to protection against disease caused by emerging variants through elicitation of effector functions.

immunology↗

bioRxiv2022

Fecal Microbiota Restoration Modulates the Microbiome in Inflammation-Driven Colorectal Cancer

Chronic inflammation of the colon (colitis) is a known risk factor for inflammatory-driven colorectal cancers (idCRC), and intestinal microbiota has been implicated in the etiology of id-CRC. Manipulation of the microbiome is a clinically viable therapeutic approach to limiting id-CRC. To understand the microbiome changes that occur over time in id-CRC, we used a mouse model of idCRC with the treatment of azoxymethane (AOM) and dextran sodium sulfate (DSS) and measured the microbiome over time using 16S rRNA amplicon sequencing. We included cohorts where the microbiome was restored using cage bedding swapping and where the microbiome was depleted using antibiotics to compare to untreated animals. We identified consistent increases in Akkermansia in mice receiving horizontal microbiome transfer (HMT), while the control cohort had consistent longitudinal increases in Anaeroplasma and Alistipes. Additionally, fecal lipocalin-2 (Lcn-2) concentrations were elevated in unrestored animals compared to restored and antibiotic-treated counterparts following HMT. These observations suggest a potential role for Akkermansia, Anaeroplasma, and Alistipes in regulating colonic inflammation in id-CRC.

microbiology↗

bioRxiv2022

Deep learning-enabled design of synthetic orthologs of a signaling protein

Evolution-based deep generative models represent an exciting direction in understanding and designing proteins. An open question is whether such models can represent the constraints underlying specialized functions that are necessary for organismal fitness in specific biological contexts. Here, we examine the ability of three different models to produce synthetic versions of SH3 domains that can support function in a yeast stress signaling pathway. Using a select-seq assay, we show that one form of a variational autoencoder (VAE) recapitulates the functional characteristics of natural SH3 domains and classifies fungal SH3 homologs hierarchically by function and phylogeny. Locality in the latent space of the model predicts and extends the function of natural orthologs and exposes amino acid constraints distributed near and far from the SH3 ligand-binding site. The ability of deep generative models to specify orthologous function in vivo opens new avenues for probing and engineering protein function in specific cellular environments.

molecular biology↗

bioRxiv2022

Genomic footprints of bottleneck in landlocked salmon population

At the end of the last ice age, several Atlantic salmon populations got caught up in the lakes and other small waterbodies of the Northern Hemisphere. Therefore, the pattern of evolution shaping the landlocked salmon populations is different from the other anadromous salmons, which migrate between the sea and rivers. According to the theories of population genetics, the effect of genetic drift is expected to be more pronounced in the former compared to the latter. Here we examined this using the whole genome data of landlocked and anadromous salmon populations of Norway. Our results showed a 50-80% reduction in the genomic heterozygosity in the landlocked compared to anadromous salmon populations. The number and total size of the runs of homozygosity (RoH) segments of landlocked salmons were 2 to 8-fold higher than those of their anadromous counterparts. We found the former had a higher ratio of nonsynonymous-to-synonymous diversities than the latter. The investigation also revealed a significant elevation of homozygous deleterious Single Nucleotide Variants (SNVs) in the landlocked salmon compared to the anadromous populations. All these results point to a significant reduction in the population size of the landlocked salmons, which might have started after the last glacial epoch. Previous studies on terrestrial vertebrates observed similar signatures of a bottleneck when the populations from Island and the mainland were compared. Since landlocked waterbody such as ponds and lakes are geographically analogous to Islands for fish populations, the findings of this study suggest the similarity in the patterns of evolution between the two.

evolutionary biology↗

bioRxiv2022

DNA bridging explains sub-diffusive movement of chromosomal loci in bacteria

Chromosomal loci in bacterial cells show a robust sub-diffusive scaling of the mean square displacement, MSD({tau}) [~]{tau} , with < 0.5. On the other hand, recent experiments have also shown that DNA-bridging Nucleoid Associated Proteins (NAPs) play an important role in chromosome organisation and compaction. Here, using polymer simulations we investigate the role of DNA bridging in determining the dynamics of chromosomal loci. We find that bridging compacts the polymer and reproduces the sub-diffusive elastic dynamics of monomers at timescales shorter than the bridge lifetime. Consistent with this prediction, we measure a higher exponent in a NAP mutant ({Delta}H-NS) compared to wild-type E. coli. Furthermore, bridging can reproduce the rare but ubiquitous rapid movements of chromosomal loci that have been observed in experiments. In our model the scaling exponent defines a relationship between the abundance of bridges and their lifetime. Using this and the observed mobility of chromosomal loci, we predict a lower bound on the average bridge lifetime of around 5 seconds. Significance StatementThe bacterial chromosome exhibits dynamics that cannot be explained by simple polymer models. In particular, the mean square displacement of individual chromosomal loci exhibits a power law scaling with an exponent less than that predicted by polymer theory. Here, we use polymer simulations and experiments to show that DNA bridging by Nucleoid Associated Proteins can explain these anomalous dynamics. Consistent with this, we show that in the absence of the bridging protein H-NS, the scaling exponent increases. Chromosomal loci also display rare rapid movements not explainable by polymer theory, even accounting for the viscoelasticity of the cytoplasm. Our simulations show that bridging can additionally explain this behaviour. Finally, we predict a lower bound on the average bridge lifetime within cells.

biophysics↗

bioRxiv2022

An antibody-drug conjugate targeting GPR56 demonstrates efficacy in preclinical models of colorectal cancer

Antibody-drug conjugates (ADCs) have become an increasingly successful class of anticancer therapy, particularly within the past few years. Though ADCs are in clinical trials for colorectal cancer (CRC), a candidate has yet to be approved. CRC continues to be a leading cause of cancer-related death, emphasizing the need to identify novel target antigens for ADC development. GPR56, a member of the 7TM receptor family, is upregulated in colorectal tumors compared to normal tissues and located on the surface of CRC cells, making it a promising ADC target. Furthermore, high GPR56 expression occurs in tumors that are microsatellite stable, negative for the CpG methylator phenotype, and show chromosomal instability. We previously reported the generation of a high affinity GPR56-specific monoclonal antibody, 10C7, and we have now mapped the epitope to the C-terminal end of the extracellular domain, proximal to the GPCR proteolysis site. Here, we describe the development of a duocarmycin-conjugated 10C7 ADC. 10C7 co-internalized with GPR56 and trafficked to the lysosomes of CRC cells, which is critical for efficient ADC payload release. Evaluation of the ADC in a panel of CRC cell lines and tumor organoids with different levels of GPR56 expression showed the ADC selectively induced cytotoxicity at low nanomolar concentrations in a GPR56-dependent manner. A nontargeting control ADC showed minimal to no activity. Furthermore, GPR56 ADC exhibited significant antitumor efficacy against GPR56-expressing patient-derived xenograft models of CRC. This study provides rationale for the development of a GPR56-targeted ADC approach to potentially treat a large fraction of CRC patients.

cancer biology↗